CN113024450A - Dithio-methyl cobalt (III) complex and preparation method and application thereof - Google Patents
Dithio-methyl cobalt (III) complex and preparation method and application thereof Download PDFInfo
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- CN113024450A CN113024450A CN202110370955.6A CN202110370955A CN113024450A CN 113024450 A CN113024450 A CN 113024450A CN 202110370955 A CN202110370955 A CN 202110370955A CN 113024450 A CN113024450 A CN 113024450A
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
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Abstract
The invention discloses a dithiomethyl ester cobalt (III) complex and a preparation method and application thereof, wherein the cobalt (III) complex has a chemical formula of [ Co [ [ III ]III(L)2]·NO3Wherein HL is: (Z) -2- (phenyl (pyridin-2-yl) methylene) hydrazine carbothiomethyl ester. The cobalt (III) complex is simple to prepare, has obvious fluorescence in the visible spectrum region of 450-650 nm, and can be used for in vitro cell imaging and in vivo imaging. The complex has micromolar anticancer activity which is obviously superior to that of cisplatin. Further proteomics studies revealed that the ability of the complexes to perform their anti-cancer capacity is likely to be through inhibition of tumor cellsQuantitative metabolism. The complex of the invention can be used for imaging and treating cancer, and has good application value.
Description
Technical Field
The invention relates to a cobalt complex, in particular to a dithiomethyl cobalt (Co) (III) complex and a preparation method and application thereof.
Background
For decades, transition metal complexes have been the focus of attention in medicinal chemistry due to their broad coordination geometry, number and type of coordinating metal ions, variable redox states, and choice of coordinating ligands. Cobalt is an essential trace element found in all animals and is used as a cofactor for vitamin B12. Thus, it can regulate DNA synthesis and maintain normal functions of the nervous system and brain. There is also evidence that vitamin B12 is essential for fatty acid and amino acid metabolism and proper red blood cell formation. The coordination chemistry of cobalt is mainly determined by co (ii) and co (iii) derivatives. Having a low spin d6The cobalt (III) complex with electronic configuration can be reduced to d7Cobalt (II) complexes, thus facilitating the leaving of the ligand. Thus, co (iii)/co (ii) is commonly used to design and develop redox-activated metal prodrugs. Recently, many cobalt (III) complexes have found potential application in medicine. For example, the cobalt (III) complex of diacetone ethylene diimine (Doxovir) has recently completed phase II clinical trials as an effective biocide.
On the other hand, dithiocarbamate schiff base ligands, whose general structure is similar to tridentate heterocyclic thiocarbamamines and ligands, have recently received much attention for their antiproliferative, anti-amoebic and antibacterial activities. Moreover, these ligands have both soft sulfur and hard nitrogen donor atoms, which can coordinate with various metal ions to form metal complexes with interesting physicochemical properties and enhanced biological properties. Therefore, in the field of medicinal inorganic chemistry, Co complexes with dithiocarbamate schiff base ligands show broad prospects as anticancer agents.
Cellular imaging of metal-based complexes can provide useful information about their potential biological applications. In the case of cancer treatment, compound imaging not only provides information about the exact tumor location, size, shape and relationship to surrounding tissue, but also allows real-time monitoring of therapeutic agents and their release or activation in the tumor, thereby allowing better treatment planning and prediction of treatment response. The application discloses a dithiomethyl ester Co (III) complex which not only has good anti-cancer capability in vitro and in vivo, but also can be used for living cells or biological imaging outside vitro.
Disclosure of Invention
The present invention provides a compound capable of chelating cobalt ionsZ) A ligand of (E) -2- (phenyl (pyridine-2-yl) methylene) hydrazine carbodithiomethyl ester, and a dithiomethyl ester cobalt (III) complex is synthesized by utilizing the ligand.
The technical scheme for realizing the purpose of the invention is as follows:
a dithio-methyl cobalt (III) complex with a chemical formula of [ CoIII(L)2]·NO3Wherein HL is: (Z) -2- (phenyl (pyridin-2-yl) methylene) hydrazine carbodithiomethyl ester; the Co (II) metal coordinates with the ligand, the hydrogen on HL is removed, the ligand becomes anion, so the chemical formula is expressed by L; at the same time, co (ii) is rapidly oxidized in solution to co (iii) complexes due to air oxidation.
The structural formula of the dithiomethyl ester cobalt (III) complex is as follows:
x-ray single crystal diffraction shows that the dithio-methyl ester cobalt (III) complex belongs to a triclinic system and a space groupP-1; the unit cell parameters are:a (Å) 9.6521(3), b (Å) 10.1324(3), c (Å) 16.8711(6), α (o) 80.874(6), β(o) 80.754(6), γ (o) 88.934 (6); the central metal + 3-valent cobalt ion in the complex and two mercaptan type modes of HL form a hexa-coordination structure.
The preparation method of the cobalt (III) complex shown in the formula is as follows:
mixing Co (NO)3)2·6H2O is added to a mixture containingZ) -2- (phenyl (pyridin-2-yl) methylene) hydrazine carbodithiomethyl ester in methanol, stirring at room temperature for 10 min; then standing at room temperature, crystallizing, and collecting crystals to obtain the dithiomethyl cobalt (III) complex;
the Co (NO)3)2·6H2O and (Z) -2- (phenyl (pyridin-2-yl) methylene) hydrazine carbodithiomethyl ester in a molar ratio of 1: 2;
the above (A) toZ) The ratio of (E) -2- (phenyl (pyridin-2-yl) methylene) hydrazine carbothiomethyl ester to methanol solution was 1 mmol:10 mL.
During preparation, the raw materials can be added according to the multiple of the mixture ratio.
The invention also aims to provide the application of the cobalt (III) dithiomethylester complex in cancer cell imaging, and researches show that the complex can be enriched in mitochondria of pancreatic cancer cells (BxPC-3).
It is another object of the present invention to provide the use of said cobalt (III) dithiomethylester complexes for in vivo imaging.
The invention also aims to provide the application of the cobalt (III) dithiomethylester complex in preparing anti-cancer (such as pancreatic cell carcinoma) medicaments.
The invention has the advantages that:
(1) through simple experimental steps and experimental conditions, the method has high efficiencyZ) -2- (phenyl (pyridin-2-yl) methylene) hydrazine carbodithiomethyl ester ligands and their cobalt (III) complexes.
(2) The cobalt (III) complexes of the invention can be used for both in vitro and in vivo imaging.
(3) The cobalt (III) complex can effectively kill cancer cells and shows good anti-cancer capability in vivo.
Drawings
FIG. 1 is a schematic diagram of the crystal structure of a cobalt (III) dithiomethylester complex of the present invention. For simplicity, solvent water molecules are deleted.
FIG. 2 is a co-localization image of human pancreatic cell carcinoma cells co-incubated with the cobalt (III) dithiomethylester complex of the present invention and the mitochondrial dye MitoTracker Deep FM.
FIG. 3 is a photograph of an image of a nude mouse injected with cobalt (III) dithiomethylester complex.
FIG. 4 is a graph showing the effect of different doses of cobalt (III) dithiomethylester complex on the growth volume of transplanted tumors in nude mice of human pancreatic cell carcinoma (CFPAC-1).
FIG. 5 is a graph of the body weight effect of different doses of cobalt (III) dithiomethylester complex on human pancreatic cell carcinoma (CFPAC-1) xenografts.
Figure 6 is differential accumulation proteins of GO functional class.
Figure 7 is GO enrichment analysis differentially expressed proteins.
FIG. 8 is a pathway analysis of differentially expressed proteins based on the KEGG database.
Detailed Description
The technical solution of the present invention will be further described in detail with reference to specific examples.
3- (4, 5-Dimethylthiazol-2-yl) -2, 5-diphenyltetrazolium bromide (MTT), phenyl (pyridin-2-yl) methanone, hydrazine carbothiomethyl ester and Co (NO)3)2·6H2O was purchased from Sigma-Aldrich. All remaining reagents and solvents were obtained from commercial sources and used without further purification.
（1）（Z) -synthesis and characterization of 2- (phenyl (pyridin-2-yl) methylene) hydrazine carbodithiomethyl ester ligand (HL):
by refluxing phenyl (pyridin-2-yl) methanone (0.92 g, 5 mmol) and hydrazine carbothiomethyl ester (0.61 g, 5 mmol) in MeOH for 1 h to give a ligand: (Z) -2- (phenyl (pyridin-2-yl) methylene) hydrazine carbothiomethyl ester as a yellow solution. Slow evaporation of the solvent at 4 ℃ gave a yellow product of HL in 1.19 g (82%). Calculated value C14H13N3S2(287.40) C, 58.51, H, 4.56 and N, 14.62. Found value of C, 58.22; H, 4.71; N, 14.32。m/z: 286.06 [M – H]+。
(2) Synthesis and structural characterization of Dithio methyl ester Co (III) Complex:
adding 5 mmol of Co (NO)3)2·6H2O was added to a solution of 10 mmol of HL ligand in methanol (100 mL) and stirred at room temperature for 10 min. The mixed solution was then left to stand at room temperature, and a brown massive dithiomethyl ester co (iii) complex was obtained by slowly evaporating the filtrate solvent, with a yield of 63%. Calculated value C28H30CoN7O6S4(747.26) C, 45.00, H, 3.97 and N, 13.12. Found C, 45.67, H, 3.56, N, 13.58.
And (3) single crystal structure characterization: data for the dithiomethyl ester co (iii) complex was collected on a Bruker SMART Apex II CCD diffractometer with a Mo-K α source of λ = 0.71073 a at room temperature. The structure of the complex was solved by a direct method and structurally optimized using the SHELXTL 5.1 software package. And (4) refining anisotropic thermal vibration parameters of all non-hydrogen atoms. Selected dithiomethyl Co (III) complexes [ CoIII(L)2]·NO3·3H2The O crystal parameters and bonding parameters are listed in tables 1 and 2.
TABLE 1 Crystal data for the dithiomethyl Co (III) complex;
table 2. bond length (a) and bond angle (q) of the dithiocarbamate mixed-valence copper complex;
x-ray single crystal diffraction shows that the dithio-methyl ester cobalt (III) complex belongs to a triclinic system and a space groupP-1. As shown in figure 1, the central metal + 3-valent cobalt ion in the complex forms a hexa-coordination structure with two thiol modes of HL.
(3) In-vitro anti-pancreatic cancer activity study of dithio-methyl cobalt (III) complex:
human pancreatic cancer cells (CFPAC-1, BxPC-3 and AsPC-1) and human normal embryonic lung fibroblasts (WI-38) were cultured in a complete medium containing 10% fetal bovine serum and 1% streptomycin/penicillin in an incubator containing 5% CO at 37 ℃. As can be seen in Table 3, IC for the Co (III) complexes50IC with values significantly lower than HL ligand50Values indicate that the anticancer activity of HL ligands is significantly affected by cobalt metal coordination. In addition, the Co (III) complex showed better in vitro anti-pancreatic cancer activity than cisplatin, IC for CFPAC-1, BxPC-3 and AsPC-1 cells, Co (III) complex50The values are respectively 8.2-, 4.1-and 3.9-fold lower than those of cisplatin.
TABLE 3 IC inhibition of human pancreatic cancer cell line growth by cobalt (III) dithiomethylester complex50Value (48 h,. mu.M);
(4) dithiomethyl ester cobalt (III) complex cellular imaging studies:
cellular imaging of metal-based complexes can provide useful information about their potential biological applications. Several metal complexes with intrinsic fluorescence, such as ir (iii), re (i) and zn (ii) complexes, can facilitate cell imaging in living cells. As shown in FIG. 2, confocal fluorescence microscopy was able to observe the imaging ability of cobalt (III) dithiomethylester complex in BxPC-3 cells of human pancreatic cancer. Co-localization studies using MitoTracker Deep Red FM showed that the green and Red signals largely combined to form a yellow color, confirming the accumulation of cobalt (III) dithiomethylester complex primarily in the mitochondrial region. Targeting mitochondria has significant advantages. Because mitochondria serve as a source of power for eukaryotic cells, mitochondrial dysfunction can prevent rapid growth of cancer cells and even lead to their death. And the anti-cancer drugs in mitochondria can avoid the nuclear excision repair mechanism, thereby restoring DNA drug addicts. In addition, mitochondria located in tumor cells are more prone to mitochondrial dysfunction than normal cells.
(5) Dithiomethyl ester cobalt (III) complex in vivo imaging studies:
the small animal living body imaging technology adopts a high-sensitivity refrigeration CCD matched with a special imaging dark box and image processing software, so that the distribution condition of the medicine in a living body organism can be directly monitored. Injecting the Co (III) complex into the abdominal cavity of a BALB/c nude mouse at a dose of 4 mg/kg, and obtaining the fluorescence imaging under the same exposure intensity and exposure time after injecting the medicine for 0, 30, 60 and 120 min respectively. Imaging with 455-495 nm excitation and 535 nm emission. Immediately after the injection of the dithiomethyl ester cobalt (III) complex, there was no fluorescence signal in vivo. As shown in fig. 3, after 30 minutes, strong in vivo fluorescence was observed, revealing the potential role of cobalt (III) dithiomethylester complexes in bioimaging, which is not limited to in vitro or living cells. After 2 hours, although the in vivo fluorescence decreased, it was still evident that the half-life of the cobalt (III) dithiomethylester complex was long, and has potential for in vivo imaging.
(6) Anti-pancreatic cancer effect of cobalt (III) dithiomethylester complex in vivo:
firstly, a CFPAC-1 xenograft tumor model of human pancreatic cell carcinoma is established. The operation is as follows: taking CFPAC-1 cells in logarithmic growth phase, inoculating the cells under the right axilla of 30 nude mice under aseptic condition, wherein the inoculation amount of the cells is 5 multiplied by 106One/only. Measuring the diameter of the transplanted tumor by using a vernier caliper until the tumor grows to 100 mm3On the left and right, 30 tumor-bearing nude mice with good growth state and good tumor size uniformity were selected and randomly divided into 3 groups of 10 mice each, i.e., a control group, a cobalt (III) dimethyldithiocarbamate complex high dose group (4 mg/kg), and a cobalt (III) dimethyldithiocarbamate complex low dose group (2 mg/kg). As shown in FIG. 4, after day 15 of administration, tumor volumes were reduced in the 2 mg/kg and 4 mg/kg dose groups relative to the control group (P)<0.05); while the body weights of the mice in the 2 mg/kg and 4 mg/kg dose groups were not significantly different from those of the mice in the control group (FIG. 5). These results indicate that cobalt (III) dithiomethylester complexes have an effect on the treatment of CFPAC-1 tumors of human pancreatic cancer.
(7) Proteomics research of dithiomethyl ester cobalt (III) complex:
proteomic analysis is a high resolution and high throughput process that can provide advanced information on the protein level related to disease or biological processes, and this knowledge is very useful for revealing the potential anti-cancer mechanisms of therapeutic agents. Thus, in order to obtain the mechanism of action of cobalt (III) dithiomethylester complexes, proteomic analysis based on Tandem Mass Tags (TMT) was performed.
To obtain the biological effect of differentially expressed proteins, GO analysis was performed on cobalt (III) dithiomethylester complexes, a technique that employs the Gene Ontology classification system to interpret Gene sets, and assigns genes into a series of predefined classes based on their functional properties. GO analysis provides a general description framework for functional annotation and classification of gene datasets. The method comprises the following three aspects: cellular components, molecular functions and biological processes. As shown in FIG. 6, cellular component analysis showed that most of the differential proteins were of the cell part, organelle part, organelle, membrane and protein-containing complex, based on > 40% gene percentage in GO entry. For molecular functions, the major differential proteins belong to binding and catalytic activity. The major differential proteins in biological processes are stress to stimulus, biological regulation, cellular process, metabolic process and cellular component organization or biogenesis. To determine if differentially expressed proteins were significantly enriched in certain functional classes, we further performed enrichment analysis of the differentially expressed proteins using the GO classification. The 10 most abundant GO items are shown in fig. 7. Further, a significantly enriched KEGG pathway was investigated and signal transduction and metabolic pathways significantly affected by cobalt (III) dithiomethylester complex treatment could be identified. As shown in fig. 8, the 10 most important pathways of action are: microbial metabolism in secondary environments, Metabolic pathways, Carbon metabolism, Biosynthesis of secondary metabolites, Citrate cycles (TCA cycle), Valine, leucine and isoluteine degradation (Valine, leucine and isoleucine degradation), proteosomes (Proteasome), Thermogenesis (Thermogenesis), Oxidative phosphorylation and Epstein-Barr virus infection (EB virus infection). From the above 10 action pathways, we can find that the cobalt (III) dithiomethylester complex acts on cancer cells mainly through energy metabolic pathways.
Claims (6)
1. A dithio-methyl-ester cobalt (III) complex, which is characterized in that the chemical formula of the complex is [ CoIII(L)2]·NO3Wherein HL is: (Z) -2- (phenyl (pyridin-2-yl) methylene) hydrazine carbodithiomethyl ester; the Co (II) metal coordinates with the ligand, the hydrogen on HL is removed, the ligand becomes anion, so the chemical formula is expressed by L;
the structural formula of the complex is as follows:
x-ray single crystal diffraction shows that the dithio-methyl ester cobalt (III) complex belongs to a triclinic system and a space groupP-1; the unit cell parameters are:a (Å) 9.6521(3), b (Å) 10.1324(3), c (Å) 16.8711(6), α (o) 80.874(6), β (o) 80.754(6), γ (o) 88.934 (6); the central metal + 3-valent cobalt ion in the complex and two mercaptan type modes of HL form a hexa-coordination structure.
2. The process for preparing a cobalt (III) dimethyldithiocarbamate complex according to claim 1, wherein: mixing Co (NO)3)2·6H2O is added to a mixture containingZ) -2- (phenyl (pyridin-2-yl) methylene) hydrazine carbodithiomethyl ester in methanol, stirring at room temperature for 10 min; then standing at room temperature, crystallizing, and collecting crystals to obtain the dithiomethyl cobalt (III) complex.
3. The process for preparing a cobalt (III) dimethyldithiocarbamate complex according to claim 2, wherein:
the Co (NO)3)2·6H2O and (Z) -2- (phenyl (pyridin-2-yl) methylene) hydrazine carbodithiomethyl ester in a molar ratio of 1: 2;
the above (A) toZ) The ratio of (E) -2- (phenyl (pyridin-2-yl) methylene) hydrazine carbothiomethyl ester to methanol solution was 1 mmol:10 mL.
4. Use of a cobalt (III) dithiomethyl ester complex according to claim 1, wherein: the dithiomethyl cobalt (III) complex has obvious fluorescence in the green region of a visible spectrum of 450-600 nm, can be used for fluorescence imaging of in vitro cancer cells and preparing a cancer cell fluorescence probe.
5. Use of a cobalt (III) dithiomethyl ester complex according to claim 1, wherein: the dithiomethyl cobalt (III) complex is excited by 455-495 nm wavelength to generate obvious fluorescence in vivo, and can be used for in vivo imaging.
6. Use of a cobalt (III) dithiomethyl ester complex according to claim 1, wherein: application in preparing antitumor drugs.
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